Procedure for the decarboxylation of 3,5-bis(haloalkyl)-pyrazole-4-carboxylic acid derivatives

ABSTRACT

A new process for the preparation of 3,5-bis(haloalkyl)-pyrazole derivatives of the general formula (I) 
     
       
         
         
             
             
         
       
     
     is described, resulting from the reaction of 3,5-bis(haloalkyl)-pyrazole-4-carboxylic acid derivatives of the general formula (Ha) 
     
       
         
         
             
             
         
       
     
     with a copper compound and a base at elevated temperature
 
wherein
         R 1  is selected from H, C 1-12 -alkyl, C 3-8 -cycloalkyl, C 6-18 -aryl, C 7-19 -arylalkyl or C 7-19 -alkylaryl, CH 2 CN, CH 2 CX 3 , CH 2 COOH, CH 2 COO(C 1-12 )-alkyl, and   X is independently of each other F, Cl, Br, I;   R 2  and R 3  are selected independently of each other from C 1 -C 6 -haloalkyl.

The present invention concerns the decarboxylation of3,5-bis(haloalkyl)-pyrazole-4-carboxylic acid derivatives for thesynthesis of 3,5-bis(haloalkyl)-pyrazole derivatives.

3,5-bis(haloalkyl)-pyrazole derivatives are important building blocksfor the preparation of crop protection chemicals, as those described inWO 2007/014290, WO 2008/013925, WO 2008/013622, WO 2008/091594, WO2008/091580, WO 2009/055514, WO 2009/094407, WO 2009/094445, WO2009/132785, WO 2010/037479, WO 2010/065579, WO 2010/066353, WO2010/123791, WO 2010/149275, WO 2011/051243, WO 2011/085170, WO2011/076699.

Decarboxylation reactions of 4-carboxylic acid pyrazoles bearing onehaloalkyl substituent are poorly developed: only two references can befound in the literature. Indeed, the resulting products are generallyvery volatile, thus very difficult to isolate.

5-Methyl-1-phenyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid istransformed into 5-methyl-1-phenyl-3-trifluoromethyl pyrazole byreaction with copper powder in quinoline (K. Tanaka et al., Bull. Chem.Soc. Jpn., 1986, 2631-2632), but the yield merely reaches 32%.

Maggio et al. describe the decarboxylation of5-amino-1-phenyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Eur.J. Med. Chem., 2008, 2386-2394) by heating it neat at its melting pointfor one hour with a low yield of 30%.

No method is described for the decarboxylation of a 4-carboxylic acidpyrazole bearing more than one haloalkyl substituent.

Guillou et al. describe a copper-catalyzed protodecarboxylation onpyrazoles (Tetrahedron 2010, 66, 2654-2663) using Cu₂O in the presenceof 1,10-phenanthroline and cesium carbonate. The reaction is carried outin DMF and under harsh conditions (microwave irradiation for 2 h at 200°C.). Metal-catalyzed protodecarboxylation reactions are described byGoossen et al. (Synthesis, 2012, 184-193) using copper and silvercatalysts. These reactions are performed on aromatic and heteroaromaticcarboxylic acids, however this reaction is not shown for the substrateshaving bis(haloalkyl)-substituents. Bis(haloalkyl)-substituents onheteroaromatic carboxylic acids are known to effect decarboxylationreactions in a negative way (e.g. very low yield or no yield).

The present invention has for objective to provide an efficient methodfor the decarboxylation of 3,5-bis(haloalkyl)-pyrazole-4-carboxylic acidderivatives avoiding the disadvantages of the methods described above.

Surprisingly, 3,5-bis(haloalkyl)-pyrazole derivatives of the generalformula (I)

can be prepared by reacting 3,5-bis(haloalkyl)-pyrazole-4-carboxylicacid derivatives of the general formula (IIa)

with a copper compound and a base at elevated temperaturewherein

-   -   R¹ is selected from H, C₃₋₈-cycloalkyl, C₆₋₁₈-aryl,        C₇₋₁₉-arylalkyl or C₇₋₁₉-alkylaryl, CH₂CN, CH₂CX₃, CH₂COOH,        CH₂COO(C₁₋₁₂)-alkyl, and    -   X is independently of each other F, Cl, Br, I;    -   R² and R³ are selected independently of each other from        C₁-C₆-haloalkyl.

Pyrazoles according to formula (I) can be made in good yield and purityso that the processes according to the invention overcomes thedisadvantages of the processes described in the state of the art.

A preferred embodiment of the present invention relates to a process forpreparing pyrazoles of formula (I),

wherein

-   -   R¹ is selected from H, CH₂CN, CH₂COO—(C₁₋₁₂)-alkyl, and    -   R² and R³ are selected independently of each other from CF₃,        CF₂H, CF₂Cl.

An especially preferred embodiment of the present invention relates to aprocess for preparing pyrazoles of formula (I),

wherein

-   -   R¹ is selected from H, CH₃, CH₂COO—(C₁₋₁₂)-alkyl, and    -   R² and R³ are selected independently of each other from CF₃,        CF₂H, CF₂Cl.

Furthermore preferred is an embodiment of the present invention whichrelates to a process for preparing pyrazoles of formula (I),

wherein

-   -   R¹ is H or CH₃.

Furthermore preferred is an embodiment of the present invention whichrelates to a process for preparing pyrazoles of formula (I),

wherein

-   -   R² is CF₂H.

GENERAL DEFINITIONS

In the context of the present invention, the term “halogens” (Hal),unless defined differently, comprises those elements which are selectedfrom the group comprising fluorine, chlorine, bromine and iodine,preferably fluorine, chlorine and bromine, more preferably fluorine andchlorine.

Optionally substituted groups may be mono- or polysubstituted, where thesubstituents in the case of polysubstitutions may be the same ordifferent.

Haloalkyl: straight-chain or branched alkyl groups having 1 to 6 andpreferably 1 to 3 carbon atoms (as specified above), where some or allof the hydrogen atoms in these groups may be replaced by halogen atomsas specified above, for example (but not limited to) C₁-C₃-haloalkylsuch as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl,fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl,dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl,1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,2-chloro-2-fluoroethyl, 2-chloro, 2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and1,1,1-trifluoroprop-2-yl. This definition also applies to haloalkyl aspart of a composite substituent, for example haloalkylaminoalkyl etc.,unless defined elsewhere. Preference is given to alkyl groupssubstituted by one or more halogen atoms, for example trifluoromethyl(CF₃), difluoromethyl (CHF₂), CF₃CH₂, CF₂Cl or CF₃CCl₂.

Alkyl groups in the context of the present invention, unless defineddifferently, are linear, branched or cyclic saturated hydrocarbylgroups. The definition C1-C12-alkyl encompasses the widest range definedherein for an alkyl group. Specifically, this definition encompasses,for example, the meanings of methyl, ethyl, n-, isopropyl, n-, iso-,sec- and t-butyl, n-pentyl, n-hexyl, 1,3-dimethylbutyl,3,3-dimethylbutyl, n-heptyl, n-nonyl, n-decyl, n-undecyl or n-dodecyl.

Alkenyl groups in the context of the present invention, unless defineddifferently, are linear, branched or cyclic hydrocarbyl groupscontaining at least one single unsaturation (double bond). Thedefinition C₂-C₁₂-alkenyl encompasses the widest range defined hereinfor an alkenyl group. Specifically, this definition encompasses, forexample, the meanings of vinyl; allyl (2-propenyl), isopropenyl(1-methylethenyl); but-1-enyl (crotyl), but-2-enyl, but-3-enyl;hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl; hept-1-enyl,hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl, hept-6-enyl;oct-1-enyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl,oct-7-enyl; non-1-enyl, non-2-enyl, non-3-enyl, non-4-enyl, non-5-enyl,non-6-enyl, non-7-enyl, non-8-enyl; dec-1-enyl, dec-2-enyl, dec-3-enyl,dec-4-enyl, dec-5-enyl, dec-6-enyl, dec-7-enyl, dec-8-enyl, dec-9-enyl;undec-1-enyl, undec-2-enyl, undec-3-enyl, undec-4-enyl, undec-5-enyl,undec-6-enyl, undec-7-enyl, undec-8-enyl, undec-9-enyl, undec-10-enyl;dodec-1-enyl, dodec-2-enyl, dodec-3-enyl, dodec-4-enyl, dodec-5-enyl,dodec-6-enyl, dodec-7-enyl, dodec-8-enyl, dodec-9-enyl, dodec-10-enyl,dodec-11-enyl; buta-1,3-dienyl or penta-1,3-dienyl.

Alkynyl groups in the context of the present invention, unless defineddifferently, are linear, branched or cyclic hydrocarbyl groupscontaining at least one double unsaturation (triple bond). Thedefinition C₂-C₁₂-alkynyl encompasses the widest range defined hereinfor an alkynyl group. Specifically, this definition encompasses, forexample, the meanings of ethynyl (acetylenyl); prop-1-ynyl andprop-2-ynyl.

Cycloalkyl: monocyclic, saturated hydrocarbyl groups having 3 to 8 andpreferably 3 to 6 carbon ring members, for example (but not limited to)cyclopropyl, cyclopentyl and cyclohexyl. This definition also applies tocycloalkyl as part of a composite substituent, for examplecycloalkylalkyl etc., unless defined elsewhere.

Aryl groups in the context of the present invention, unless defineddifferently, are aromatic hydrocarbyl groups which may have one, two ormore heteroatoms selected from O, N, P and S. The definition C₆₋₁₈-arylencompasses the widest range defined herein for an aryl group having 5to 18 skeleton atoms, where the carbon atoms may be exchanged forheteroatoms. Specifically, this definition encompasses, for example, themeanings of phenyl, cycloheptatrienyl, cyclooctatetraenyl, naphthyl andanthracenyl; 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl,3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl,4-isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,1,2,4-triazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl and1,3,4-triazol-2-yl; 1-pyrrolyl, 1-pyrazolyl, 1,2,4-triazol-1-yl,1-imidazolyl, 1,2,3-triazol-1-yl, 1,3,4-triazol-1-yl; 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl,1,3,5-triazin-2-yl and 1,2,4-triazin-3-yl.

Arylalkyl groups (aralkyl groups) in the context of the presentinvention, unless defined differently, are alkyl groups which aresubstituted by aryl groups, may have one C₁₋₈-alkylene chain and mayhave, in the aryl skeleton, one or more heteroatoms selected from O, N,P and S. The definition C₇₋₁₉-aralkyl group encompasses the widest rangedefined herein for an arylalkyl group having a total of 7 to 19 atoms inthe skeleton and alkylene chain. Specifically, this definitionencompasses, for example, the meanings of benzyl and phenylethyl.

Alkylaryl groups (alkaryl groups) in the context of the presentinvention, unless defined differently, are aryl groups which aresubstituted by alkyl groups, may have one C₁₋₈-alkylene chain and mayhave, in the aryl skeleton, one or more heteroatoms selected from O, N,P and S. The definition C₇₋₁₉-alkylaryl group encompasses the widestrange defined herein for an alkylaryl group having a total of 7 to 19atoms in the skeleton and alkylene chain. Specifically, this definitionencompasses, for example, the meanings of tolyl or 2,3-, 2,4-, 2,5-,2,6-, 3,4- or 3,5-dimethylphenyl.

The term intermediate used in the context of the present inventiondescribes the substances which occur in the process according to theinvention and are prepared for further chemical processing and areconsumed or used therein in order to be converted to another substance.The intermediates can often be isolated and intermediately stored or areused without prior isolation in the subsequent reaction step. The term“intermediate” also encompasses the generally unstable and short-livedintermediates which occur transiently in multistage reactions (stagedreactions) and to which local minima in the energy profile of thereaction can be assigned.

The inventive compounds may be present as mixtures of any differentisomeric forms possible, especially of stereoisomers, for example E andZ isomers, threo and erythro isomers, and optical isomers, but ifappropriate also of tautomers. Both the E and the Z isomers aredisclosed and claimed, as are the threo and erythro isomers, and alsothe optical isomers, any mixtures of these isomers, and also thepossible tautomeric forms.

Process Description

The decarboxylation step is performed in the presence of a coppercompound, a base, optionally water and optionally solvent.

The copper compound is selected from Cu, Cu₂O, CuO, CuCl, CuI; preferredare Cu and Cu₂O.

The amount of copper compound can vary within a large range; preferablyit is within 0.01 and 1 equivalents for 1 equivalent of pyrazolic acid;more preferably between 0.05 to 0.5 quivalents; most preferably are 0.05equivalents.

The base used for the process according to the invention is an organicor inorganic base. A single compound or a mixture of different compoundscan be used as base. The inorganic base is selected from a groupcomprising cesium carbonate and potassium carbonate The organic base isselected from a group comprising quinoline, pyridines, alkylpyridines,phenanthroline, N-methylmorpholine, NMP, DMF, dimethylacetamid.Preference is given to using organic bases. Preference is also given tousing a mixture of bases. Especially preferred is a mixture of organicbases.

The mixtures of organic bases are for instance binary mixtures, ternarymixtures and quaternary mixtures. Ternary mixtures are for instance1,10-phenanthroline, NMP and quinoline; 1,10-phenanthroline, pyridineand NMP; 1,10-phenanthroline, DMF and pyridine; 1,10-phenanthroline,quinoline and pyridine; 1,10-phenanthroline, quinoline and DMF;1,10-phenanthroline, N-methylmorpholine and quinoline;1,10-phenanthroline N-methylmorpholine and DMF; 1,10-phenanthroline,N-methylmorpholine and pyridine. Binary mixtures are for instance1,10-phenanthroline and NMP; 1,10-phenanthroline and pyridine;1,10-phenanthroline and DMF; 1,10-phenanthroline and quinoline;1,10-phenanthroline and N-methylmorpholine; 1,10-phenanthroline andalkylpyridines; 1,10-phenanthroline and dimethylacetamid.

Preferred are ternary mixtures of organic bases. Preferred is a mixtureof 1,10-phenanthrolin, quinoline and NMP.

For the ternary mixtures of organic bases the volume ratio between anytwo compounds, independently of each other, is from 100:1 to 1:100,preferably from 50:1 to 1:50, more preferably, 25:1 to 1:25 and mostpreferably 15:1 to 1:15.

Further volume ratio between any two compounds of the ternary mixturesof organic bases, independently of each other, which can be usedaccording to the present invention with increasing preference in theorder given are 100:1 to 1:100, 90:1 to 1:90, 80:1 to 1:80, 70:1 to1:70, 60:1 to 1:60, 40:1 to 1:40, 30:1 to 1:30, 10:1 to 1:10, 5:1 to1:5.

A preferred volume ratio for the ternary mixture of organic bases is1:50:50 to 1:1:1; more preferred is 1:5:20 to 1:5:5.

Especially preferred is a volume ratio for the mixture of1,10-phenanthroline (A), quinoline (B) and NMP (C) of 1:5:20 to 1:5:5((A):(B):(C)).

The amount of organic base can vary within a large range; preferably itis within 0.1 and 30 equivalents for 1 equivalent of pyrazolic acid;more preferably between 0.5 to 10 equivalents. Most preferably are 6equivalents of organic base.

The reaction time of the process according to the invention is generallynot of critical importance and can depend on the reaction volume;preferably it is within the range of 3 to 12 h.

The temperature of the process according to the invention is rangingfrom 40 to 190° C.; preferably from 60° C. to 180° C., more preferablyfrom 80° C. to 175° C.

Optionally a solvent is used for the decarboxylation reaction accordingto the invention. The solvent is for instance mesitylene ordichlorobenzene. The amount of solvent can vary within a large range;preferably it is within 0.1 to 40 equivalents for 1 equivalent ofpyrazolic acid; more preferably between 0.2 to 20 equivalents. Mostpreferably the reaction according to the invention is performed withoutadditional solvent.

Optionally water is used for the decarboxylation reaction according tothe invention. The amount of water can vary within a large range;preferably it is within 0.001 and 0.1 equivalents for 1 equivalent ofpyrazolic acid, more preferably between 0.02 to 0.08 equivalents.

Decarboxylation can also be performed under acidic conditions. Preferredacids for this step are: H₂SO₄, HCl, HBr, HI, CH₃COOH, CF₃COOH, CF₃SO₃H,CH₃SO₃H, p-toluenesulfonic acid, oleum, HF. The amount of acid can varywithin a large range; preferably it is within 0.1 and 1.5 equivalents,more preferably between 0.5 to 1.2 equivalents for 1 equivalent ofpyrazolic acid. Acidic decarboxylation proceeds preferably in water. Theacidic decarboxylation is performed at a temperature ranging from 50 to220° C., preferably at a temperature ranging from 70° C. to 210° C.,more preferably from 80° C. to 190° C. The reaction time is generallynot of critical importance and can depend on the reaction volume;preferably it is within the range of 2 to 7 h.

Decarboxylation can also be performed under basic conditions. Preferredinorganic bases are LiOH, KOH, NaOH, K₂CO₃, Cs₂CO₃, Ba(OH)₂, NH₄OH,n-BuONa. Especially preferred bases are K₂CO₃ and Cs₂CO₃. The amount ofbase can vary within a large range; preferably it is within 0.1 and 1.5equivalents, more preferably between 0.5 to 1 equivalents for 1equivalent of pyrazolic acid. The basic decarboxylation is performed ata temperature ranging from 40 to 150° C., preferably at a temperatureranging from 50° C. to 140° C., more preferably from 80° C. to 120° C.The reaction time is generally not of critical importance and can dependon the reaction volume; preferably it is within the range of 1 to 7 h.Optionally the decarboxylation under basic conditions can be performedin the presence of high boiling solvents like NMP, quinoline,dimethylacetamid, 1,10-phenanthrolin or mesitylene.

3,5-bis(haloalkyl)pyrazoles of the formula (II)

in which

-   -   R¹ is selected from H, C₃₋₈-cycloalkyl, C₆₋₁₈-aryl,        C₇₋₁₉-arylalkyl or C₇₋₁₉-alkylaryl, CH₂CN, CH₂CX₃, CH₂COOH,        CH₂COO—(C₁₋₁₂)-alkyl and    -   X is independently of each other F, Cl, Br, I,    -   R² and R³ are selected independently of each other from        C₁-C₆-haloalkyl groups,    -   R⁴ is selected from H, Hal, COOH, (C═O)OR⁵, CN and (C═O)NR⁵R⁶,        where R⁵ and R⁶ are selected independently of each other from        C₁₋₁₂-alkyl, C₃₋₈-cycloalkyl, C₆₋₁₈-aryl, C₇₋₁₉-arylalkyl and        C₇₋₁₉-alkylaryl, or R⁵ and R⁶ form together with the nitrogen        atom to which they are bonded a five- or six-membered ring        can be prepared as follows:

In step A), α,α-dihaloamines of the formula (III),

in which X is Cl or F and R², R⁵ and R⁶ are as described above, arereacted with compounds of the formula (IV),

in which the radicals are each as defined above and, in step B), theproduct is reacted with hydrazines of the formula (V),

in which R¹ is as defined above.

In step A), α,α-dihaloamines of the formula (III) are reacted,optionally in the presence of a Lewis acid [L], with compounds of theformula (IV).

Compounds of the general formula (III) are e.g.1,1,2,2-tetrafluoroethyl-N,N-dimethylamine (TFEDMA),1,1,2,2-tetrafluoroethyl-N,N-diethylamine,1,1,2-trifluoro-2-(trifluoromethyl)ethyl-N,N-dimethylamine,1,1,2-trifluoro-2-(trifluoromethyl)ethyl-N,N-diethylamine (Ishikawa'sreagent), 1,1,2-trifluoro-2-chloroethyl-N,N-dimethylamine and1,1,2-trifluoro-2-chloroethyl-N,N-diethylamine (Yarovenko's reagent).

Compounds of the general formula (III) are used as aminoalkylatingagents. α,α-Dihaloamines such as TFEDMA and Ishikawa's reagent arecommercially available or can be prepared (cf. Yarovenko et al., Z h.Obshch. Khim. 1959, 29, 2159, Chem. Abstr. 1960, 54, 9724h or Petrov etal., J. Fluor. Chem. 109 (2011) 25-31).

The α,α-dihaloamine is first reacted with Lewis acid [L], for exampleBF₃, AlCl₃, SbCl₅, SbF₅, ZnCl₂, and then the mixture of the compound ofthe formula (IV) and a base is added, in substance or dissolved in asuitable solvent (cf. WO 2008/022777).

The reaction is effected at temperatures of 20° C. to +40° C.,preferably at temperatures of 20° C. to +30° C., more preferably at −10to 20° C. and under standard pressure. Due to the hydrolysis sensitivityof the α,α-dihaloamines, the reaction is conducted in anhydrousapparatuses under inert gas atmosphere.

The reaction time is not critical and may, according to the batch sizeand temperature, be selected within a range between a few minutes andseveral hours.

1 mol of the Lewis acid [L] is reacted with equimolar amounts of theα,α-dihaloamine of the formula (III).

The aminoalkylation (reaction with compound of the formula (III)) ispreferably effected in the presence of a base. Preference is given toorganic bases such as trialkylamines, pyridines, alkylpyridines,phosphazenes and 1,8-diazabicyclo[5.4.0]undecene (DBU); alkali metalhydroxides, for example lithium hydroxide, sodium hydroxide or potassiumhydroxide, alkali metal carbonates (Na₂CO₃, K₂CO₃) and alkoxides, forexample NaOMe, NaOEt, NaOt-Bu, KOt-Bu or KF.

1 mol of the base for the compound of the formula (IV) is reacted withequimolar amounts of the α,α-dihaloamine of the formula (III).

Preference is given to using keto compounds of the formula (IV) selectedfrom the group comprising ethyl 4,4,4-trifluoro-3-oxobutanoates, methyl4,4,4-trifluoro-3-oxobutanoates, ethyl 4,4-difluoro-3-oxobutanoates,ethyl 4-chloro-4,4-difluoro-3-oxobutanoates, 1,1,1-trifluoroacetone or4-chloro-4,4-difluoro-3-oxobutanenitriles.

Said keto compounds of the formula (IV) are commercially available orcan be prepared according to procedures described in the literature.

Suitable solvents are, for example, aliphatic, alicyclic or aromatichydrocarbons, for example petroleum ether, n-hexane, n-heptane,cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, andhalogenated hydrocarbons, for example chlorobenzene, dichlorobenzene,dichloromethane, chloroform, tetrachloromethane, dichloroethane ortrichloroethane, ethers such as diethyl ether, diisopropyl ether, methyltert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran,1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles such asacetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile;amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoramide;sulphoxides such as dimethyl sulphoxide or sulphones such as sulpholane.Particular preference is given, for example, to THF, acetonitriles,ethers, toluene, xylene, chlorobenzene, n-hexane, cyclohexane ormethylcyclohexane, and very particular preference, for example, toacetonitrile, THF, ether or dichloromethane

The intermediates of the formula (VII) are used in the cyclization stepB) with hydrazines of the general formula (V) without prior workup.

Alternatively, the intermediates of the formula (VII) can be isolatedand characterized by suitable workup steps and optionally furtherpurification.

The cyclization in step B) is effected at temperatures of −40° C. to 80°C., preferably at temperatures of −10° C. to 60° C., more preferably at−10° C. to 50° C. and under standard pressure.

The reaction time is not critical and may, according to the batch size,be selected within a relatively wide range.

Typically, the cyclization step B) is effected without changing thesolvent.

1 to 2 mol, preferably 1 to 1.5, of the hydrazines of the formula (V)per 1 mol of the compound of the formula (IV) are used.

Preference is given to performing all reaction steps of the process inthe same solvent.

Said hydrazines of the formula (V) are commercially available or can beprepared as described, for example, in Niedrich et al., Journal fuerPraktische Chemie (Leipzig) (1962), 17 273-81; Carmi, A.; Pollak,Journal of Organic Chemistry (1960), 25 44-46.

Suitable solvents are, for example, aliphatic, alicyclic or aromatichydrocarbons, for example petroleum ether, n-hexane, n-heptane,cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, andhalogenated hydrocarbons, for example chlorobenzene, dichlorobenzene,dichloromethane, chloroform, tetrachloromethane, dichloroethane ortrichloroethane, ethers such as diethyl ether, diisopropyl ether, methyltert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran,1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; alcohols such asmethanol, ethanol, isopropanol or butanol, nitriles such asacetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile;amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoramide;sulphoxides such as dimethyl sulphoxide or sulphones such as sulpholane.Particular preference is given, for example, to acetonitrilestoluene,xylene, chlorobenzene, n-hexane, cyclohexane or methylcyclohexane, andvery particular preference, for example, to acetonitriles, THF, tolueneor xylene. After the reaction has ended, for example, the solvents areremoved and the product is isolated by filtration, or the product isfirst washed with water and extracted, the organic phase is removed andthe solvent is removed under reduced pressure.

The compounds of the formula (II) where R⁴═COOR⁵ can then be convertedto pyrazole acids of the formula (Ha) R⁴═COOH.

The conversion is generally performed under acidic or basic conditions.

For acidic hydrolysis, preference is given to mineral acids, for exampleH₂SO₄, HCl, HSO₃Cl, HF, HBr, HI, H₃PO₄ or organic acids, for exampleCF₃COOH, p-toluenesulphonic acid, methanesulphonic acid,trifluoromethanesulphonic acid. The reaction can be accelerated by theaddition of catalysts, for example FeCl₃, AlCl₃, BF₃, SbCl₃, NaH₂PO₄.The reaction can likewise be performed without addition of acid, only inwater.

Basic hydrolysis is effected in the presence of inorganic bases such asalkali metal hydroxides, for example lithium hydroxide, sodium hydroxideor potassium hydroxide, alkali metal carbonates, for example Na₂CO₃,K₂CO₃ and alkali metal acetates, for example NaOAc, KOAc, LiOAc, andalkali metal alkoxides, for example NaOMe, NaOEt, NaOt-Bu, KOt-Bu oforganic bases such as trialkylamines, alkylpyridines, phosphazenes and1,8-diazabicyclo[5.4.0]undecene (DBU). Preference is given to theinorganic bases, for example NaOH, KOH, Na₂CO₃ or K₂CO₃.

The process step is performed preferably within a temperature range from20° C. to 150° C., more preferably at temperatures of 30° C. to 110° C.,most preferably at 30° C. to 80° C.

The process step is generally performed under standard pressure.Alternatively, however, it is also possible to work under vacuum orunder elevated pressure (for example reaction in an autoclave withaqueous HCl).

The reaction time may, according to the batch size and the temperature,be selected within a range between 1 hour and several hours.

The reaction step can be performed in substance or in a solvent.Preference is given to performing the reaction in a solvent. Suitablesolvents are, for example, selected from the group comprising water,alcohols such as methanol, ethanol, isopropanol or butanol, aliphaticand aromatic hydrocarbons, for example n-hexane, benzene or toluene,which may be substituted by fluorine and chlorine atoms, such asmethylene chloride, dichloroethane, chlorobenzene or dichlorobenzene;ethers, for example diethyl ether, diphenyl ether, methyl tert-butylether, isopropyl ethyl ether, dioxane, diglyme, dimethylglycol,dimethoxyethane (DME) or THF; nitriles such as methyl nitrile, butylnitrile or phenyl nitrile; amides we dimethylformamide (DMF) orN-methylpyrrolidone (NMP) or mixtures of such solvents, particularpreference being given to water, acetonitrile, dichloromethane andalcohols (ethanol).

EXAMPLES Example 13-(difluoromethyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole

3-(difluoromethyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylicacid (8.60 mmol, 2.1 g), Cu₂O (65 mg, 0.45 mmol), 1,10-Phenanthrolin(176 mg, 0.90 mmol) and NMP (15 mL), quinoline (5 mL) and H₂O (2 drops)were heated for 10 h at 160° C. The reaction mixture was diluted withwater and the product extracted three times with diethyl ether. Theorganic phase was washed with 1M HCl-solution. The organic phase wasdried and the solvent removed under atmospheric pressure with VigreuxColummn. The product N-Methyl-5-trifluormethyl-3-difluoromethylpyrazol(0.85 g, 4.25 mmol, 50%) was purified via distillation in vacuum, (b.p.:45-46° C./27 mbar).

¹H NMR (CDCl₃, 300 MHz, 25° C.): δ=6.84 (s, 1H), 6.66 (t, 1H, CHF₂,J_(H-F)=55 Hz), 4.02 (s, 3H, N—CH₃) ppm.

¹³C NMR (CDCl₃, 75 MHz, 25° C.): δ=145.6 (t, J_(C-F)=30 Hz), 133.3 (q,T_(C-F)=39.6 Hz), 119.5 (q, CF₃, T_(C-F)=267.2 Hz), 110.3 (t, CHF₂,T_(C-F)=233.2 Hz), 105.2 (q, T_(C-F)=2 Hz), 38.3 (q, N—CH3, T_(C-F)=1.6Hz) ppm.

¹⁹F NMR (CDCl₃, 282 MHz, 25° C.): δ=−61.5 (CF₃), −113.0 (CHF₂) ppm.

Examples 2 to 7 were all prepared according to the protocol of Example1.

Example 2 3,5-bis(difluoromethyl)-1-methyl-1H-pyrazole

Yield 78%, oil, b.p.=78-80° C., 28 mbar.

¹H NMR (CDCl₃, 300 MHz, 25° C.): δ=6.73 (t, 1H, CHF₂, J_(H-F)=53.4 Hz),6.69 (s, 1H), 6.66 (t, 1H, CHF₂, J_(H-F)=54.9 Hz), 4.01 (s, 3H, N—CH₃)ppm.

¹³C NMR (CDCl₃, 75 MHz, 25° C.): δ=145.6 (t, T_(C-F)=30 Hz), 136.5 (t,T_(C-F)=26.6 Hz), 110.6 (t, CHF₂, T_(C-F)=234.1 Hz), 108.2 (t, CHF₂,T_(C-F)=236.5 Hz), 104.7 (m), 38.1 (s, N—CH₃) ppm.

¹⁹F NMR (CDCl₃, 282 MHz, 25° C.): δ=−112.5 (CHF₂, T_(F-H)=54.9 Hz),−113.7 (CHF₂, J_(F-H)=53.3 Hz) ppm.

Example 3 3-(difluoromethyl)-1-methyl-5-(pentafluoroethyl)-1H-pyrazole

Yield 63%. Oil, b.p.=53-54° C., 28 mbar.

¹H NMR (CDCl₃, 300 MHz, 25° C.): δ=6.84 (s, 1H, Harom), 6.67 (t, 1H,CHF₂, J_(H-F)=54.8 Hz), 4.05 (s, 3H, N—CH₃) ppm.

¹³C NMR (CDCl₃, 75 MHz, 25° C.): δ=146.0 (t, T_(C-F)=30.1 Hz), 131.2 (t,T_(C-F)=28.9 Hz), 118.5 (qt, CF₂-CF₃, J¹ _(C-F)=285.7 Hz, J² _(C-F)=37.3Hz), 110.2 (t, CHF₂, J_(C-F)=234.8 Hz), 109.8 (tq, CF₂-CF₃, J¹_(C-F)=252.7 Hz, J² _(C-F)=40.6 Hz), 106.9 (brs), 39.2 (brs, N—CH₃) ppm.

¹⁹F NMR (CDCl₃, 282 MHz, 25° C.): δ=−84.4 (CF₂ CF ₃), −111.1 (CF ₂CF₃),−113.0 (CHF₂, J_(F-H)=54.8 Hz) ppm.

Example 4 3-(difluoromethyl)-1-phenyl-5-(pentafluoroethyl)-1H-pyrazole

Yield 88%, isolated via column chromatographie on SiO₂ usingPentane/Et₂O 95:5 mixture.

¹H NMR (CDCl₃, 300 MHz, 25° C.): δ=7.54-7.43 (m, 5H), 7.03 (brs, 1H),6.76 (t, 1H, CHF₂, J_(H-F)=54.6 Hz) ppm.

¹³C NMR (CDCl₃, 75 MHz, 25° C.): δ=147.4 (t, J_(C-F)=30.4 Hz), 139.1(s), 132.4 (t, J_(C-F)=28.1 Hz), 130.2 (s), 129.1 (s, CHphenyl), 126.7(s), 118.5 (qt, CF₂-CF₃, J¹ _(C-F)=286.3 Hz, J² _(C-F)=36.8 Hz), 110.4(t, CHF₂, J_(C-F)=235.3 Hz), 109.5 (tq, CF₂-CF₃, J¹=252.0 Hz, J²_(C-F)=40.4 Hz), 107.5 (brs) ppm.

¹⁹F NMR (CDCl₃, 282 MHz, 25° C.): δ=−83.9 (CF₂ CF ₃), −107.1 (CF ₂CF₃),−113.0 (CHF₂, J_(F-H)=54.6 Hz) ppm.

Example 5 3-(difluoromethyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole

Yield 84%, isolated via column chromatographie on SiO₂ using Pentan/Et₂O95:5 mixture.

¹H NMR (CDCl₃, 300 MHz, 25° C.): δ=7.55-7.48 (m, 5H), 7.07 (brs, 1H),6.78 (t, 1H, CHF₂, J_(H-F)=54.6 Hz) ppm.

¹³C NMR (CDCl₃, 75 MHz, 25° C.): δ=146.9 (t, J_(C-F)=30.5 Hz), 138.4(s), 134.2 (q, J_(C-F)=40.0 Hz), 130.0 (s), 129.3 (s, CH), 125.7 (s,CH), 119.2 (q, CF₃, J_(C-F)=269.4 Hz), 110.4 (t, CHF₂, J_(C-F)=235.1 Hz,106.4 (brs, CH pyrazol) ppm.

¹⁹F NMR (CDCl₃, 282 MHz, 25° C.): δ=−58.4 (CF₃), −112.9 (CHF₂,J_(F-H)=54.6 Hz) ppm.

Example 61-tert-butyl-3-(difluoromethyl)-5-(trifluoromethyl)-1H-pyrazole

Yield 83%, oil, b.p.=68-69° C., 32 mbar.

¹H NMR (CDCl₃, 300 MHz, 25° C.): δ=6.94 (brs, 1H, Harom), 6.68 (t, 1H,CHF₂, J_(H-F)=54.8 Hz), 1.69 (s, 9H, CH₃) ppm.

¹³C NMR (CDCl₃, 75 MHz, 25° C.): δ=143.5 (t, J_(C-F)=30.4 Hz), 132.7 (q,J_(C-F)=40.1 Hz), 119.9 (q, CF₃, J_(C-F)=268.9 Hz), 110.8 (t, CHF₂,J_(C-F)=233.9 Hz), 108.0 (q, J_(C-F)=3.8 Hz), 64.2 (s, tBu), 29.8 (q,tBuCH₃, J_(C-F)=2.1 Hz) ppm.

¹⁹F NMR (CDCl₃, 282 MHz, 25° C.): δ=−55.6 (CF₃), −112.3 (CHF₂,J_(F-H)=54.9 Hz) ppm.

Example 7 3-(difluoromethyl)-5-(pentafluoroethyl-1H-pyrazole

The N—H-5-pentafluoroethyl-3-difluoromethylpyrazol, yield 44%, Oilb.p.=63-65° C., 55 mbar.

¹H NMR (CDCl₃, 300 MHz, 25° C.): δ=11.87 (brs, 1H, NH), 6.87 (brs, 1H),6.80 (t, 1H, CHF₂, J_(H-F)=54.7 Hz) ppm.

¹³C NMR (CDCl₃, 75 MHz, 25° C.): δ=141.5 (brs, C_(IV)arom), 139.5 (brs,C_(IV)arom), 118.4 (qt, CF₂-CF₃, J¹ _(C-F)=285.4 Hz, J² _(C-F)=37.3 Hz),109.9 (tq, CF₂-CF₃, J¹ _(C-F)=252.2 Hz, J² _(C-F)=40.1 Hz), 108.4 (t,CHF₂, J_(C-F)=238.2 Hz), 104.9 (brs, CHpyrazol)ppm.

¹⁹F NMR (CDCl₃, 282 MHz, 25° C.): δ=−85.1 (CF₂ CF ₃), −113.5 (CF ₂CF₃),−113.8 (CHF₂, J_(F-H)=54.7 Hz) ppm.

Example 8 3-(difluoromethyl)-5-(trifluoromethyl)-1H-pyrazole

A mixture of N-tert-butyl-3-(difluoromethyl)-5-(trifluoromethyl)pyrazole (0.10 g, 0.41 mmol), anisole (0.13 g, 0.14 ml, 1.23 mmol) andtrifluoroacetic acid (2 ml) was stirred and heated to 90° C. for 16 h.The reaction mixture was cooled to ambient temperature, neutralised bythe addition of a solution of sodium hydroxide (210 mmol, 8.4 g) inwater (30 mL) until the pH=8. The aqueous layer was extracted withdiethyl ether (3×30 mL). The combined organic layers were washed withbrine (30 mL), dried over sodium sulphate and the solvent was evaporatedat atmospheric pressure. The crude material was purified by columnchromatography on silica gel with pentane/diethyl ether (gradient 100:0to 50:50) as eluent to afford pureN—H-3-(difluoromethyl)-5-(trifluoromethyl) pyrazole (0.47 g, 2.53 mmol,76%) as a colourless solid.

¹H NMR (CDCl₃, 300 MHz, 25° C.): δ=13.38 (brs, 1H, N—H), 6.84 (s, 1H,Harom), 6.79 (t, 1H, CHF₂, J_(H-F)=54.7 Hz) ppm.

¹³C NMR (CDCl₃, 75 MHz, 25° C.): δ=141.1 (brs, C_(IV)arom, C¹ and C³),120.1 (q, CF₃, T_(C-F)=268.8 Hz), 108.3 (t, CHF₂, T_(C-F)=238.2 Hz),103.6 (d, CHarom, T_(C-F)=1.6 Hz) ppm.

Example 9N-Methyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acidethyl ester

BF₃.OEt₂ (0.62 ml, 5.0 mmol) was added to a solution of TFEDMA (0.59 ml,5.0 mmol) in dry dichloromethanes (5 mil) under argon in a Teflon flask.The solution was stirred at room temperature for 15 min, before thedichloromethane was removed under reduced pressure. The residue was thentaken up in dry acetonitrile (5 ml). In a second Teflon flask, ethyltrifluoroacetoacetate (0.73 ml, 5.0 mmol) was added to a solution ofpotassium fluoride (0.88 g, 15.0 mmol) in dry acetonitrile (10 ml) andthe mixture was stirred at room temperature for 15 min. To this wereadded dropwise, at −30° C. the contents of the first flask. The reactionmixture was brought to room temperature in the cold bath and stirredovernight. Methyl hydrazine (0.32 ml, 6.0 mmol) was then added dropwiseat room temperature and the mixture was stirred overnight. The solventwas removed under reduced pressure and the residue was purified by flashchromatography on silica gel with a pentanes/diethyl ether mixture(9:1-8:2).N-Methyl-5-trifluoromethyl-3-difluoromethyl-4-pyrazolecarboxylic acidethyl ester (0.99 g, 3.64 mmol, 73%) was obtained as a yellow oil.

¹H NMR (CDCl₃, 300 MHz. 25° C.): δ=7.00 (t. 1H, CHF₂, J_(H-F)=54 Hz),4.37 (q, 2H, CH₂, J=7.2 Hz), 4.12 (s, 3H, N—CH₃), 1.37 (t, 3H, CH₃,J=7.2 Hz) ppm. ¹³C NMR (CDCl₃, 75 MHz, 25° C.): δ=160.2 (CO), 145.7 (t,C_(IV)arom, J_(C-F)=25.6 Hz), 133.2 (q, C_(IV)arom, J_(C-F)=40.3 Hz),119.0 (q, CF₃, J_(C-F)=271.2 Hz), 114.4 (C_(IV)arom), 109.0 (t, CHF₂,J_(C-F)=237.9 Hz), 61.9 (CH₂), 40.8 (q, N—CH₃, J_(C-F)=3.2 Hz), 13.8(CH₃) ppm. ¹⁹F NMR (CDCl₃, 282 MHz, 25° C.): δ=−57.6 (CF₃), −116.4(CHF₂) ppm.

Example 10N-Methyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid

N-Methyl-5-trifluoromethyl-3-difluoromethyl-4-pyrazolecarboxylic acidethyl ester (0.5 g. 1.84 mmol) in ethanol (3 mil) was admixed graduallywith an 8N aqueous sodium hydroxide solution (0.7 ml) and stirred atroom temperature for 3 h. The solvent was removed by rotary evaporation,the residue was taken up in water (10 ml) and extracted with diethylether (10 ml). Acidification to pH 1 with 1M HCl was followed byextraction with ethyl acetate (3×10 ml). The combined organic phaseswere dried over sodium sulphate and filtered, and the solvent wasremoved by rotary evaporation.N-Methyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid(0.44 g. 1.80 mmol. 98%) was isolated as a yellowish solid.

¹H NMR (CDCl₃, 300 MHz, 25° C.): δ=7.08 (t, 1H, CHF₂, J_(H-F)=53.5 Hz),4.16 (s, 3H, N—CH₃) ppm.

¹³C NMR (CDCl₃, 75 MHz, 25° C.): δ=165.5 (CO), 146.7 (t, C_(IV)arom,J_(C-F)=18.8 Hz), 134.4 (q, C_(IV)arom, J_(H-F)=30.8 Hz), 118.8 (q, CF₃,J_(C-F)=202.5 Hz), 112.9 (C_(IV)arom), 108.7 (t, CHF₂, J_(C-F)=177.0Hz), 41.1 (q, N—CH₃, J_(C-F)=2.3 Hz) ppm. ¹⁹F NMR (CDCl₃, 282 MHz, 25°C.): δ=−57.9 (CF₃), −117.3 (CHF₂, J_(F-H)=53.5 Hz) ppm.

Example 11 N—H-3-Difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylicacid ethyl ester

BF₃.OEt₂ (0.31 ml, 2.5 mmol) was added to a solution of TFEDMA (030 mL2.5 mmol) in dry dichloromethanes (2.5 ml) under argon in a Teflonflask. The solution was stirred at room temperature for 15 min. beforethe dichloromethane was removed under reduced pressure. The residue wasthen taken up in dry acetonitrile (2.5 ml). In a second Teflon flask,ethyl trifluoroacetoacetate (0.37 ml, 2.5 mmol) was added to a solutionof potassium fluorides (0.44 g, 7.5 mmol) in dry acetonitrile (5 ml) andthe mixture was stirred at room temperature for 15 min. To this wereadded dropwise, at −30° C. the contents of the first flask. The reactionmixture was brought to room temperature in the cold bath and stirredovernight. Hydrazine hydrate (0.15 ml, 3.0 mmol) was then added dropwiseat room temperature and the mixture was stirred for 24 h. The solventwas removed under reduced pressure and the residue was purified by flashchromatography on silica gel with a pentanes/diethyl ether mixture(9:1-7:3). N—H-3-Difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylicacid ethyl ester (0.48 g, 1.88 mmol, 75%) was obtained as a yellowishoil, which crystallized when left to stand.

¹H NMR (CDCl₃. 300 MHz, 25° C.): δ=11.07 (brs. 1H, NH), 7.22 (t, 1H,CHF₂, J_(H-F)=53.5 Hz), 4.39 (q, 2H, CH₂, J=6.9 Hz), 1.38 (t, 3H, CH₃,J=6.9 Hz) ppm. ¹³C NMR (CDCl₃, 75 MHz, 25° C.): δ=160.4 (CO), 142.2 (t,C_(IV)arom, J_(C-F)=18.3 Hz), 142.2 (q, C_(IV)arom, J_(C-F)=32.0 Hz),119.7 (q, CF₃, J_(C-F)=268.1 Hz), 111.7 (C_(IV)arom), 107.4 (t, CHF₂,J_(C-F)=237.5 Hz), 62.0 (CH₂), 13.7 (CH₃) ppm. ¹⁹F NMR (CDCl₃, 282 MHz,25° C.): δ=−62.5 (CF₃), −117.1 (CHF₂, J_(F-H)=53.5 Hz) ppm.

Example 12 N-Methyl-3,5-difluoromethyl-4-pyrazolecarboxylic acid ethylester

BF₃.OEt₂ (1.24 ml, 10.0 mmol) was added to a solution of TFEDMA (1.20ml, 10.0 mmol) in dry dichloromethanes (10 ml) under argon in a Teflonflask. The solution was stirred at room temperature for 15 min, beforethe dichloromethane was removed under reduced pressure. The residue wasthen taken up in dry acetonitrile (10 mil). In a second Teflon flask,ethyl 4,4-difluoroacetoacetate (1.03 ml, 10.0 mmol) was added to asolution of pyridine (1.6 ml, 20.0 mmol) in dry acetonitrile (20 ml) andthe mixture was stirred at mom temperature for 15 min. To this wereadded dropwise, at −30° C., the contents of the first flask. Thereaction mixture was brought to room temperature in the cold bath andstirred overnight. Methyl hydrazine (0.79 ml, 15.0 mmol) was then addeddropwise at room temperature and the mixture was stirred overnight. Thesolvent was removed under reduced pressure and the residue was purifiedby flash chromatography on silica gel with a pentanes/diethyl ethermixture (10:0-8:2). (10:0 to 8:2).N-Methyl-3,5-difluoromethyl-4-pyrazolecarboxylic acid ethyl ester (1.75g, 6.89 mmol, 69%) was obtained as a colourless oil, which crystallizedwhen left to stand.

¹H NMR (CDCl₃, 300 MHz, 25° C.): δ=7.48 (t, 1H, CHF₂, J_(H-F)=52.6 Hz),7.04 (t, 1H, CHF₂, J_(H-F)=53.8 Hz), 4.38 (q, 2H, CH₂, J=7.1 Hz), 4.12(s, 3H. N—CH₃), 1.39 (t, 3H, CH₃, J=7.2 Hz) ppm ¹³C NMR (CDCl₃, 75 MHz,25° C.): δ=161.1 (CO), 145.3 (t, C_(IV)arom, J_(C-F)=24.9 Hz), 138.2 (t,C_(IV)arom, J_(C-F)=24.1 Hz), 112.9 (m, C_(IV)arom), 109.1 (t, CHF₂,J_(C-F)=237.6 Hz). 107.2 (t, CHF₂, J_(C-F)=236.3 Hz), 61.5 (CH₂), 39.6(t, N—CH₃, J_(C-F)=3.1 Hz), 13.9 (CH₃) ppm. ¹⁹F NMR (CDCl₃, 282 MHz, 25°C.): δ=−117.00 (CHF₂, J_(F-H)=53.8 Hz), −117.04 (CHF₂, J_(F-H)=52.6 Hz)ppm.

Example 13 N-Methyl-3,5-difluoromethyl-4-pyrazolecarboxylic acid

N-Methyl-3,5-difluoromethyl-4-pyrazolecarboxylic acid ethyl ester (0.5g, 2.0 mmol) in ethanol (3 ml) was admixed gradually with an 8N aqueoussodium hydroxide solution (0.8 ml) and stirred at room temperature for 2h. The solvent was removed by rotary evaporation; the residue was takenup in water (10 ml) and extracted with diethyl ether (10 ml).Acidification to pH 1 with 6M HCl was followed by extraction with ethylacetate (3×10 ml). The combined organic phases were dried over sodiumsulphate and filtered, and the solvent was removed by rotaryevaporation. N-Methyl-3,5-difluoromethyl-4-pyrazolecarboxylic acid (0.44g. 1.95 mmol, 97%) was isolated as a colourless solid.

¹H NMR (CDCl₃, 300 MHz, 25° C.): δ=12.16 (brs, 1H, COOH), 7.48 (t, 1H,CHF₂, J_(H-F)=52.4 Hz). 7.08 (t, 1H, CHF₂, J_(H-F)=53.6 Hz), 4.16 (s,3H, N—CH₃) ppm. ¹³C NMR (CDCl₃, 75 MHz, 25° C.): δ=166.9 (CO), 146.4 (t,C_(IV)arom, J_(C-F)=25.1 Hz), 139.2 (t, C_(IV)arom, J_(C-F)=24.4 Hz).111.5 (C_(IV)arom), 108.8 (t, CHF₂, J_(C-F)=238.1 Hz), 106.9 (t, CHF₂,J_(C-F)=237.0 Hz). 39.9 (t, N—CH₃, J_(C-F)=3.1 Hz) ppm. ¹⁹F NMR (CDCl₃,282 MHz, 25° C.): δ=−117.1 (CHF₂, J_(F-H)=52.6 Hz), −117.3 (CHF₂,J_(F-H)=53.7 Hz) ppm.

Example 14 N—H-3,5-Difluoromethyl-4-pyrazolecarboxylic acid ethyl ester

BF₃.OEt₂ (1.85 ml, 15.0 mmol) was added to a solution of TFEDMA (1.76ml, 15.0 mmol) in dry dichloromethanes (15 ml) under argon in a Teflonflask. The solution was stirred at room temperature for 15 min, beforethe dichloromethane was removed under reduced pressure. The residue wasthen taken up in dry acetonitrile (15 ml). In a second Teflon flask,ethyl 4,4-difluoroacetoacetate (1.55 ml, 15 mmol) was added to asolution of potassium fluorides (2.61 g. 45 mmol) in dry acetonitrile(30 ml) and the mixture was stirred at room temperature for 15 min. Tothis were added dropwise, at −30° C., the contents of the first flask.The reaction mixture was brought to mom temperature in the cold bath andstirred overnight. Hydrazine hydrate (1.1 ml, 22.5 mmol) was then addeddropwise at room temperature and the mixture was stirred overnight. Thesolvent was removed under reduced pressure and the residue was purifiedby flash chromatography on silica gel with a pentanes/diethyl ethermixture (9:1-7:3). N—H-3,5-Difluoromethyl-4-pyrazolecarboxylic acidethyl ester (2.02 g, 8.40 mmol, 56%) was isolated as a colourless solid.

¹H NMR (CDCl₃, 300 MHz. 25° C.): δ=7.15 (t, 2H, CHF₂, J_(H-F)=53.6 Hz).4.39 (q. 2H, CH₂, J=7.1 Hz), 1.39 (t. 3H, CH₃, J=7.1 Hz) ppm. ¹³C NMR(CDCl₃, 75 MHz, 25° C.): δ=161.1 (CO), 143.8 (t. C_(IV)arom,J_(C-F)=23.1 Hz), 111.6 (C_(IV)arom), 108.2 (t, CHF₂, J_(C-F)=238.4 Hz),61.7 (CH₂), 13.9 (CH₃) ppm. ¹⁹F NMR (CDCl₃, 282 MHz, 25° C.): δ=−117.3(CHF₂, J_(F-H)=53.6 Hz) ppm

1. Process for synthesis of a 3,5-bis(haloalkyl)-pyrazole derivative offormula (I)

comprising reacting a 3,5-bis(haloalkyl)-pyrazole-4-carboxylic acidderivative of formula (Ha)

with a copper compound and a base at elevated temperature wherein R¹ isselected from H, C₁₋₁₂-alkyl, C₃₋₈-cycloalkyl, C₆₋₁₈-aryl,C₇₋₁₉-arylalkyl or C₇₋₁₉-alkylaryl, CH₂CN, CH₂CX₃, CH₂COOH,CH₂COO(C₁₋₁₂)-alkyl, and X is independently of each other F, Cl, Br, I;R² and R³ are selected independently of each other from C₁-C₆-haloalkyl.2. Process according to claim 1, wherein R¹ is selected from H,C₁₋₁₂-alkyl, CH₂CN, CH₂COO—(C₁₋₁₂)-alkyl, and R² and R³ are selectedindependently of each other from CF₃, CF₂H, CF₂Cl.
 3. Process accordingto claim 1, wherein R¹ is selected from H, CH₃, CH₂COO—(C₁₋₁₂)-alkyl,and R² and R³ are selected independently of each other from CF₃, CF₂H,CF₂Cl.
 4. Process according to claim 1, wherein R¹ is H or CH₃. 5.Process according to claim 1, wherein R² is CF₂H.
 6. Process accordingto claim 1, wherein the base is a mixture of 1,10-phenanthrolin,quinoline and NMP.
 7. Process according to claim 1, wherein the base isa mixture of 1,10-phenanthrolin and NMP.
 8. Process according to claim1, wherein the base is a mixture of 1,10-phenanthrolin and quinoline. 9.Process according to claim 1, further comprising adding water. 10.Process according to claim 1, wherein between 0.02 to 0.08 equivalentsof water are added for 1 equivalent of pyrazolic acid.
 11. Processaccording to claim 1, wherein reaction temperature is 40° C. to 190° C.12. Process according to claim 1, wherein reaction temperature is 60° C.to 180° C.
 13. Process according to claim 1, wherein reactiontemperature is 80° C. to 175° C.